GPR119 is a GPCR expressed predominantly in pancreatic β-cells and gastrointestinal enteroendocrine cells. Metformin is a first-line treatment for type 2 diabetes with minimal weight loss in humans. In this study, we investigated the effects of GSK2041706, a GPR119 agonist, and metformin as a monotherapy or in combination on body weight in a diet-induced obese (DIO) mouse model. Relative to vehicle controls, 14-day treatment with GSK2041706 (30mg/kg, bid) or metformin at 30 and 100mg/kg b.i.d. alone caused 7.4%, 3.5% and 4.4% (all p<0.05) weight loss, respectively. The combination of GSK2041706 with metformin at 30mg/kg or 100mg/kg resulted in 9.5% and 16.7% weight loss, respectively. The combination of GSK2041706 and metformin at 100mg/kg caused significantly greater weight loss than the projected additive weight loss of 11.8%. This body weight effect was predominantly due to a loss of fat. Cumulative food intake was reduced by 17.1% with GSK2041706 alone and 6.6% and 8.7% with metformin at 30 and 100mg/kg, respectively. The combination of GSK2041706 with metformin caused greater reductions in cumulative food intake (22.2% at 30mg/kg and 37.5% at 100mg/kg) and higher fed plasma GLP-1 and PYY levels and decreased plasma insulin and GIP levels compared to their monotherapy groups. In addition, we characterized the effect of GSK2041706 and metformin as monotherapy or in combination on neuronal activation in the appetite regulating centers in fasted DIO mice. In conclusion, our data demonstrate the beneficial effects of combining a GPR119 agonist with metformin in the regulation of body weight in DIO mice.
- The American Society for Pharmacology and Experimental Therapeutics